Vasoactive intestinal peptide (VIP) was first discovered, isolated and purified from porcine intestine. [U.S. Pat. No. 3,879,371]. The peptide has twenty-eight (28) amino acids and bears extensive homology to secretin and glucagon. [Carlquist et al., Horm. Metab. Res., 14, 28-29 (1982)]. The amino acid sequence of VIP is as follows: ##STR1##
VIP is known to exhibit a wide range of biological activities throughout the gastrointestinal tract and circulatory system. In light of its similarity to gastrointestinal hormones, VIP has been found to stimulate pancreatic and biliary secretion, hepatic glycogenolysis, glucagon and insulin secretion and to activate pancreatic bicarbonate release. [Kerrins, C. and Said, S. I., Proc. Soc. Exp. Biol. Med., 142, 1014-1017 (1972), Domschke, S. et al., Gastroenterology, 73, 478-480 (1977)].
Neurons containing VIP have been localized by immunoassay in cells of the endocrine and exocrine systems, intestine and smooth muscle. [Polak, J. M. et al., Gut, 15, 720-724 (1974)]. VIP has been found to be a neuroeffector causing the release of several hormones including prolactin [Frawley, L. S., et al., Neuroendocrinology, 33, 79-83 (1981)], thyroxine [Ahren, B., et al., Nature, 287, 343-345 (1980)], and insulin and glucagon [Schebalin, M., et al., Am. J. Physiology E., 232, 197-200 (1977)]. VIP has also been found to stimulate renin release from the kidney in vivo and in vitro. [Porter, J. P., et al. Neuroendocrinology, 36, 404-408 (1983)]. VIP has been found to be present in nerves and nerve terminals in the airways of various animal species and man. [Dey, R. D., and Said, S. I., Fed. Proc., 39, 1062 (1980), Said, S. I., et al., Ann. N.Y. Acad. Sciences, 221, 103-114 (1974)]. VIP's cardiovascular and bronchopulmonary effects are of interest as VIP has been found to be a powerful vasodilator and potent smooth muscle relaxant, acting on peripheral, pulmonary, and coronary vascular beds. [Said, S. I., et al., Clin. Res., 20, 29 (1972)]. VIP has been found to have a vasodilatory effect on cerebral blood vessels. [Lee, T. J. and Berszin, I., Science, 224, 898-900 (1984)]. In vitro studies demonstrated that vasoactive intestinal peptide, applied exogenously to cerebral arteries induced vasodilation, suggesting VIP as a possible transmitter for cerebral vasodilation. [Lee, T. and Saito, A., Science, 224, 898-901 (1984)]. In the eye, VIP has also been shown to be a potent vasodilator [Nilsson, S. F. E. and Bill, A., Acta Physiol. Scand., 121, 385-392 (1984)].
VIP may have regulatory effects on the immune system. O'Dorisio et al have shown that VIP can modulate the proliferation and migration of lymphocytes. [J. Immunol., 135, 792s-796s (1985)].
Since VIP has been found to relax smooth muscle and it is normally present in airway tissues, it has been hypothesized that VIP may be an endogenous mediator of bronchial smooth muscle relaxation. [Dey, R. D. and Said, S. I., Fed. Proc., 39, 1062 (1980)]. In vitro and in vivo testing have shown VIP to relax tracheal smooth muscle and protect against bronchoconstrictor agents such as histamine and prostaglandin F.sub.2a. [Wasserman, M. A. et al., in Vasoactive Intestinal Peptide, S. I. Said, ed., Raven Press, N.Y., 1982, pp 177-184. Said, S. I. et al., Ann. N.Y. Acad. Sci., 221, 103-114 (1974)]. When giving intravenously, VIP has been found to protect against bronchoconstrictor agents such as histamine, prostaglandin F.sub.2a, leukotrienes, platelet activating factor as well as antigen-induced bronchoconstrictions. [Said, S. I., et al., supra, (1982)]. VIP has also been found to inhibit mucus secretion in human airway tissue in vitro. [Coles, S. J. et al., Am. Rev. Respir. Dis., 124, 531-536 (1981)].
In man, when administered by intravenous infusion to asthmatic patients, VIP has been shown to cause an increase in peak expiratory flow rate and protect against histamine-induced bronchodilation. [Morice, A. H. and Sever, P. S., Peptides, 7, 279-280 (1986); Morice, A. et al., The Lancet, II 1225-1227 (1983)]. The pulmonary effects observed by this intravenous infusion of VIP were, however, accompanied by cardiovascular side-effects, most notably hypotension and tachycardia and also facial flushing. When given in intravenous doses which did not cause cardiovascular effects, VIP failed to alter specific airway conductance. [Palmer et al., Thorax, 41, 663-666 (1986)]. The lack of activity was explained as being due to the low dose administered and possibly due to rapid degradation of the compound.
When administered by aerosol to humans, native VIP has been only marginally effective in protecting against histamine-induced bronchoconstriction [Altieri et al., Pharmacologist, 25, 123 (1983)]. VIP was found to have no significant effect on baseline airway parameters but did have a protective effect against histamine-induced bronchoconstriction when given by inhalation to humans. [Barnes, P. J. and Dixon, C. M. S., Am. Rev. Respir. Dis., 130, 162-166 (1984)]. VIP when given by aerosol has been reported to display no tachycardia or hypotensive effects in conjunction with the bronchodilation. [Said, S. I. et al., in Vasoactive Intestinal Peptide, S. I. Said, ed., Raven Press, N.Y., 1928, pp 185-191].
Because of the interesting and potential clinically useful biological activities of VIP, this substance has been the target of several reported synthetic programs with the goal of enhancing one or more of the properties of this molecule. Takeyama et al. have reported a VIP analog having a glutamic acid substituted for aspartic acid at position 8. This compound was found to be less potent than native VIP. [Chem. Pharm. Bull., 28, 2265-2269 (1980)]. Wendlberger et al. have disclosed the preparation of a VIP analog having norleucine substituted at position 17 for methionine. [Peptide, Proc. 16th Eur. Pept. Symp., 290-295 (1980)]. The peptide was found to be equipotent to native VIP for its ability to displace radioiodinated VIP from liver membrane preparations. Turner et al. have reported that the fragment VIP(10-28) is an antagonist to VIP. [Peptides, 7, 849-854 (1986)]. The substituted analog [4-Cl-D-Phe.sup.6,Leu.sup.17 ]-VIP has also been reported to bind to the VIP receptor and antagonize the activity of VIP. [Pandol, S. et al., Gastrointest. Liver Physiol., 13, G553-G557 (1986)]. P. Robberecht et al. have reported several VIP analogs with D-residues substituted in the N-terminus of native VIP. [Peptides, 9, 339-345 (1988)]. All of these analogs bound less tightly to the VIP receptor and showed lower activity than native VIP in c-AMP activation. S. Tachibana and O. Ito have reported several VIP analogs of the precursor molecule. [in Peptide Chem., T. Shiba and S. Sakakibara, eds., Prot. Res. Foundation, 1988, pp. 481-486]. These compounds were shown to be 1 to 3 fold more potent bronchodilators than VIP and had 1 to 2 fold more hypotensive activity. Musso et al. have also reported several VIP analogs with substitutions at positions 6-7, 9-13, 15-17, and 19-28. [Biochemistry, 27, 8174-8181 (1988); Eur. Pat. 88271141]. These compounds were found to be equal to or less potent than native VIP in binding to the VIP receptor and in biological response.